Details of the Researcher

PHOTO

Kinuko Ohneda
Section
Tohoku Medical Megabank Organization
Job title
Professor
Degree

  • 博士（医学）（東北大学）

Research Areas 1

  • Life sciences / Molecular biology /

Papers 78

  1. Exploring the association between human breast milk lipids and early adiposity rebound in children: A case-control study. International-journal

    Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

    Nutrition (Burbank, Los Angeles County, Calif.)　135　112739-112739　2025/03/08

    DOI： 10.1016/j.nut.2025.112739 　

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    OBJECTIVES: Adiposity rebound (AR) corresponds to the start of the second rise in the body mass index curve during infant growth. Early AR (before age 5) confers increased risk of adiposity and metabolic disorders but is less likely to occur in breastfed infants. Although lipids in breast milk are important in child growth, information is limited regarding which lipids are involved in AR. The object of this study was to explore the association between breast milk lipids and AR status in children. METHODS: We designed a case-control study of 184 mother-child pairs (AR cases: n = 93; controls: n = 91) included from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Breast milk was collected 1 month postpartum and comprehensive lipid analysis was performed. Partial least square-discriminant analysis was used to explore candidate lipids, and multivariable logistic regression analysis was used to evaluate associations with the AR status of children. RESULTS: We detected 667 lipid molecules in 12 lipid classes in breast milk. Partial least square-discriminant analysis revealed the association of fatty acid-hydroxy fatty acid (FAHFA) and cholesterol ester (ChE) with AR status. Multivariable logistic regression analysis showed that in pairs with exclusive breastfeeding at 1 month postpartum, FAHFA (odds ratio 1.57 [95% confidence interval, 1.06-2.32]) was positively associated with early AR, and ChE (odds ratio 0.55 [95% confidence interval, 0.36-0.86]) was negatively associated. CONCLUSIONS: Breast milk lipids (FAHFA, ChE) associated with the AR status of children, indicating the potential to regulate a child's adiposity and possible metabolic disorders in adulthood.

  2. Association Between Human Milk Oligosaccharides and Early Adiposity Rebound in Children: A Case-Control Study of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. International-journal

    Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Tomoko Tanaka, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

    The Journal of nutrition　2025/03/07

    DOI： 10.1016/j.tjnut.2025.02.024 　

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    BACKGROUND: Adiposity rebound (AR) is the point when the body mass index (BMI) begins to rise again during early childhood. Early AR (before age 5) is associated with a higher risk of lifelong obesity and metabolic disorders and may be influenced by breastfeeding. Although human milk oligosaccharides (HMOs) in breast milk are crucial for child growth, their association with AR status has not been studied. OBJECTIVE: To explore breast milk HMO compositions and molecules associated with AR status in children. METHODS: In this case-control study, we included 184 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation (TMM BirThree) Cohort Study (93 AR cases, 91 controls). Breast milk was collected 1 month postpartum, and the concentration of 15 HMO molecules and alpha-diversity index (Inverse Simpson index) were quantified. Wilcoxon's rank-sum test and partial least squares-discriminant analysis (PLS-DA) identified candidate HMOs, and multivariable logistic regression analysis evaluated associations between candidate HMOs and AR status. Analyses were stratified by maternal secretor status (secretor or non-secretor). RESULTS: In secretor mothers, multivariable logistic regression showed that the Inverse Simpson index (OR, 0.54 [95% CI, 0.36-0.82]), sum of sialic acid-bound HMOs (0.61 [0.41-0.91]), and 3'-sialyllactose (0.67 [0.46-0.98]) were inversely associated with early AR in a fully adjusted model. A trend of interaction between sialyl-lacto-N-tetraose a (LSTa) and maternal secretor status on AR was observed in a fully adjusted model (P-value for interaction = 0.051). CONCLUSIONS: Alpha diversity, sialic acid-bound HMOs, and 3'SL may be involved in inhibiting AR in children of secretor mothers, and a trend of interactive effect of LSTa among maternal secretor status on AR was indicated. These findings offer novel perspectives on the associations between breastfeeding and a child's adiposity as well as potential metabolic disorders later in life. REGISTRY NUMBER/WEBSITE: https://www.umin.ac.jp/ (trial registration number: UMIN000047160).

  3. Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan. International-journal

    Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-Ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto

    Journal of human genetics　2025/01/17

    DOI： 10.1038/s10038-024-01314-w 　

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    Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

  4. Absolute quantification of eight human milk oligosaccharides in breast milk to evaluate their concentration profiles and associations with infants' neurodevelopmental outcomes. International-journal

    Keigo Sato, Yoshitaka Nakamura, Kazuhito Fujiyama, Kinuko Ohneda, Takahiro Nobukuni, Soichi Ogishima, Satoshi Mizuno, Seizo Koshiba, Shinichi Kuriyama, Shinji Jinno

    Journal of food science　89　(12)　10152-10170　2024/12

    DOI： 10.1111/1750-3841.17597 　

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    Human milk oligosaccharides (HMOs) have been positively associated with child neurodevelopment in some cohort studies. However, there is a lack of consistency in the association between HMOs and benefits to infants' brains. Moreover, the quantification methods for HMOs have not yet been standardized. In this study, we developed a quantification method for evaluating eight HMOs (2'-fucosyllactose [2'-FL], 3'-fucosyllactose [3'-FL], 3'-sialyllactose [3'-SL], 6'-sialyllactose [6'-SL], lactosialyltetrasaccharide a [LSTa], lactosialyltetrasaccharide b [LSTb], lactosialyltetrasaccharide c [LSTc], and disialyllacto-N-tetraose [DSLNT]) in breast milk. After validating the method, we applied it to 1-month breast milk samples (n = 150) from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study to assess HMO profiles in breast milk and their possible association with changes in head circumference z-score (ΔHCZ) and neurodevelopmental scores of children (as measured by the Ages and Stages Questionnaire, Third Edition). The validation demonstrated that the method had relative standard deviation ≤ 12.7% of precision and 79.5-110.9% of accuracy. Using this method, eight HMO levels (2'-FL, 0-4.74 mg/mL; 3'-FL, 0.02-1.52 mg/mL; 3'-SL, 0.07-0.32 mg/mL; 6'-SL, 0.01-0.70 mg/mL; LSTa, 0.002-0.043 mg/mL; LSTb, 0.02-0.31 mg/mL; LSTc, 0.001-0.47 mg/mL; and DSLNT, 0.09-0.71 mg/mL [min-max, all participants]) and the ratio of low secretors (16.0%) in the Japanese cohort were obtained. The obtained HMO levels in breast milk were subjected to multivariate analysis to screen for HMOs showing a positive association with ΔHCZ and neurodevelopmental scores. The results proposed that ΔHCZ was positively associated with LSTb and 2'-FL levels, whereas neurodevelopmental scores were positively associated with 2'-FL levels (among all participants) and 3'-SL and DSLNT levels (among secretor participants). This study showed that the developed method provides HMO profiles in Japanese breast milk, as well as additional information on the associations between specific HMOs and neurodevelopment, reinforcing the sum of evidence for the role of HMOs in the brain.

  5. 一般住民コホート参加者に対する遺伝性乳がん卵巣がんの遺伝情報回付事業

    湊 純子, 島田 宗昭, 栃木 実佳子, 大根田 絹子, 濱中 洋平, 宮原 周子, 渋谷 祐介, 橋本 千明, 石橋 ますみ, 重田 昌吾, 徳永 英樹

    日本婦人科腫瘍学会学術講演会プログラム・抄録集　66回　332-332　2024/07

    Publisher: (公社)日本婦人科腫瘍学会

  6. [Return of Individual Genomic Results to Germline Pathogenic Variant Carriers of Hereditary Cancer in Population Based Cohort Study].

    Kinuko Ohneda

    Gan to kagaku ryoho. Cancer & chemotherapy　51　(3)　231-236　2024/03

    ISSN： 0385-0684

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    Return of individual genomic results(ROGR)to participants in population-based biobank has been rarely conducted in research settings, and the procedure of ROGR performed in foreign countries may not be simply applied to Japanese participants, because of the difference in social background. The Tohoku Medical Megabank Project, which was launched in 2012 aiming to build a foundation of personalized genomic medicine, obtained the consent from research participants by explaining the future possibility of ROGR. After careful consideration of appropriate procedure for ROGR, individual genomic results were returned to 111 pathogenic variant(PV)carriers of hereditary breast and ovarian cancer syndrome(HBOC)or Lynch syndrome(LS)based on 50,000 whole genome sequencing(WGS)data in FY 2022. Since majority of the participants has no cancer diagnosis, participants' right to not know was carefully considered. In addition, the variants to be returned were carefully evaluated by using multiple databases, and the WGS results of the participants were further confirmed by the single- site analysis. When the genomic results were returned, the participants were informed about clinical risk surveillance at the hospital. Seventy-eight and 33 PV carriers of HBOC and LS, respectively, participated in the study. Most participants were in their 30s or 40s. Unexpectedly, validation testing results of 12 LS participants were found to be negative or variant of uncertain significance, because detecting these variants by WGS were technically challenging. Twenty-eight participants (HBOC 20, LS 8)had been diagnosed as cancer, and 6 females who had breast cancer were genetically diagnosed as HBOC and underwent or planned risk-reducing surgery. Eighteen participants refused to undergo clinical risk surveillance because of the medical expense that is not covered by health insurance and the burden of visiting the hospital. The opportunity to undergo medical surveillance should be provided to population-based cohort participants who carry actionable pathogenic variants, and ROGR to general population should be promoted to create the base of personalized genomic medicine.

  7. Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

    Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    Journal of biochemistry　2024/01/24

    DOI： 10.1093/jb/mvae008 　

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    Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.

  8. Effect of Nicotinamide Mononucleotide Concentration in Human Milk on Neurodevelopmental Outcome: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. International-journal

    Yoshie Saito, Keigo Sato, Shinji Jinno, Yoshitaka Nakamura, Takahiro Nobukuni, Soichi Ogishima, Satoshi Mizuno, Seizo Koshiba, Shinichi Kuriyama, Kinuko Ohneda, Masashi Morifuji

    Nutrients　16　(1)　2023/12/31

    DOI： 10.3390/nu16010145 　

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    (1) Background: Breast milk is the only source of nutrition for breastfed infants, but few studies have examined the relationship between breast milk micronutrients and infant neurodevelopmental outcome in exclusively breastfed infants. The aim of this study was to characterize the association between nicotinamide adenine dinucleotide (NAD)-related compounds in the breast milk of Japanese subjects and infant neurodevelopmental outcome. (2) Methods: A total of 150 mother-child pairs were randomly selected from the three-generation cohort of the Tohoku Medical Megabank in Japan. Infants were exclusively breastfed for up to 6 months. Breast milk was collected at 1 month postpartum, and the quantity of NAD-related substances in the breast milk was quantified. The mothers also completed developmental questionnaires at 6, 12, and 24 months. The relationship between the concentration of NAD-related substances in breast milk and developmental indicators was evaluated via ordinal logistic regression analysis. (3) Results: Nicotinamide mononucleotide (NMN) was quantified as the major NAD precursor in breast milk. The median amount of NMN in the breast milk was 9.2 μM. The NMN concentration in breast milk was the only NAD-related substance in breast milk that showed a significant positive correlation with neurodevelopmental outcome in infants at 24 months. (4) Conclusions: The results suggest that NMN in human milk may be an important nutrient for early childhood development.

  9. 未発症のBRCA1/2病的バリアント保持者に対するサーベイランスの課題

    濱中 洋平, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 本成 登貴和, 川目 裕, 鈴木 洋一, 長神 風二, 布施 昇男, 大根田 絹子, 山本 雅之, 石田 孝宣

    日本乳癌検診学会学術総会プログラム抄録集　33回　148-148　2023/11

    Publisher: (NPO)日本乳癌検診学会

  10. ゲノムコホート研究参加者5万人を対象としたBRCA1/2遺伝情報の回付と医療への連携

    濱中 洋平, 大根田 絹子, 川目 裕, 布施 昇男, 長神 風二, 鈴木 洋一, 山口 由美, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　31回　89-89　2023/06

    Publisher: (一社)日本乳癌学会

  11. Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants.

    Kinuko Ohneda, Yohei Hamanaka, Hiroshi Kawame, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Yumi Yamaguchi-Kabata, Muneaki Shimada, Atsushi Masamune, Yoko Aoki, Takanori Ishida, Masayuki Yamamoto

    Breast cancer (Tokyo, Japan)　30　(1)　110-120　2023/01

    DOI： 10.1007/s12282-022-01404-7 　

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    BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

  12. マスト細胞における転写因子GATA2の高度転写活性化機序の解析

    大森 慎也, 高井 淳, 森口 尚, 森 哲哉, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　95回　1P-248　2022/11

    Publisher: (公社)日本生化学会

  13. The Il6 -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for Il6 expression in murine mast cells. International-journal

    Shin'ya Ohmori, Jun Takai, Satoshi Uemura, Akihito Otsuki, Tetsuya Mori, Kinuko Ohneda, Takashi Moriguchi

    iScience　25　(9)　104942-104942　2022/09/16

    DOI： 10.1016/j.isci.2022.104942 　

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    Mast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distal cis-regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at the Il6 -39 kb region revealed its central role in LPS-induced Il6 expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distal cis-regulatory regions.

  14. 全ゲノム/全エキソーム解析による生殖細胞系列多型の探索 一般住民コホートにおけるBRCA遺伝子バリアントの探索及び結果の回付事業について(Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants)

    徳永 英樹, 安田 純, 島田 宗昭, 濱中 洋平, 重田 昌吾, 布施 昇男, 勝岡 史城, 荻島 創一, 山口 由美, 寳澤 篤, 川目 裕, 大根田 絹子, 青木 洋子, 山本 雅之, 八重樫 伸生

    日本癌学会総会記事　81回　S8-1　2022/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  15. A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

    Kinuko Ohneda, Masahiro Hiratsuka, Hiroshi Kawame, Fuji Nagami, Yoichi Suzuki, Kichiya Suzuki, Akira Uruno, Mika Sakurai-Yageta, Yohei Hamanaka, Makiko Taira, Soichi Ogishima, Shinichi Kuriyama, Atsushi Hozawa, Hiroaki Tomita, Naoko Minegishi, Junichi Sugawara, Inaho Danjoh, Tomohiro Nakamura, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Shu Tadaka, Taku Obara, Eiji Hishimuma, Nariyasu Mano, Masaki Matsuura, Yuji Sato, Masateru Nakasone, Yohei Honkura, Jun Suzuki, Yukio Katori, Yoichi Kakuta, Atsushi Masamune, Yoko Aoki, Masaharu Nakayama, Shigeo Kure, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto

    JMA journal　5　(2)　177-189　2022/04/15

    DOI： 10.31662/jmaj.2021-0156 　

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    Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

  16. The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. International-journal

    Hiroshi Kawame, Akimune Fukushima, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Jun Yasuda, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Soichi Ogishima, Takako Takai, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naoko Minegishi, Junichi Sugawara, Kichiya Suzuki, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Yayoi Aizawa, Tomoharu Tokutomi, Kayono Yamamoto, Kinuko Ohneda, Shigeo Kure, Yoko Aoki, Hideki Katagiri, Yasushi Ishigaki, Shojiro Sawada, Makoto Sasaki, Masayuki Yamamoto

    Journal of human genetics　67　(1)　9-17　2022/01

    DOI： 10.1038/s10038-021-00952-8 　

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    Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

  17. 温故知新;古くて新しいGATA転写因子研究の最前線 炎症制御因子としてのGATA2

    高井 淳, 大森 慎也, 大根田 絹子, 上村 聡志, 山本 雅之, 森口 尚

    日本生化学会大会プログラム・講演要旨集　94回　[2S12m-02]　2021/11

    Publisher: (公社)日本生化学会

  18. マウスマスト細胞における新規Il6遺伝子制御領域(Il6-DRE)の同定と解析

    大森 慎也, 森口 尚, 高井 淳, 森 哲哉, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　94回　[P-633]　2021/11

    Publisher: (公社)日本生化学会

  19. マウスマスト細胞における新規Il6遺伝子制御領域(Il6-DRE)の同定と解析

    大森 慎也, 森口 尚, 高井 淳, 森 哲哉, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　94回　[P-633]　2021/11

    Publisher: (公社)日本生化学会

  20. 温故知新;古くて新しいGATA転写因子研究の最前線 炎症制御因子としてのGATA2

    高井 淳, 大森 慎也, 大根田 絹子, 上村 聡志, 山本 雅之, 森口 尚

    日本生化学会大会プログラム・講演要旨集　94回　[2S12m-02]　2021/11

    Publisher: (公社)日本生化学会

  21. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　29回　21-21　2021/07

    Publisher: (一社)日本乳癌学会

  22. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　29回　21-21　2021/07

    Publisher: (一社)日本乳癌学会

  23. Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species. International-journal

    Vuong Cat Khanh, Toshiharu Yamashita, Kinuko Ohneda, Chiho Tokunaga, Hideyuki Kato, Motoo Osaka, Yuji Hiramatsu, Osamu Ohneda

    Scientific reports　10　(1)　17315-17315　2020/10/14

    DOI： 10.1038/s41598-020-74444-8 　

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    Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs' ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.

  24. コホート調査参加者に対するゲノム薬理学(PGx)遺伝情報の返却(回付) 個別化予防・医療の確立を目指して

    大根田 絹子, 布施 昇男, 川目 裕, 長神 風二, 平塚 真弘, 櫻井 美佳, 濱中 洋平, 鈴木 吉也, 鈴木 洋一, 山本 雅之

    日本薬学会年会要旨集　140年会　27K-pm08　2020/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  25. GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms. International-journal Peer-reviewed

    Shin'ya Ohmori, Yasushi Ishijima, Suzuka Numata, Mai Takahashi, Masataka Sekita, Taichi Sato, Keisuke Chugun, Masayuki Yamamoto, Kinuko Ohneda

    Molecular and cellular biology　39　(22)　2019/11/15

    DOI： 10.1128/MCB.00314-19 　

    ISSN： 0270-7306

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    GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FcεRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal -60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and -60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FcεRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.

  26. Mouse Tryptase Gene Expression is Coordinately Regulated by GATA1 and GATA2 in Bone Marrow-Derived Mast Cells. International-journal Peer-reviewed

    Kinuko Ohneda, Shin'ya Ohmori, Masayuki Yamamoto

    International journal of molecular sciences　20　(18)　2019/09/17

    DOI： 10.3390/ijms20184603 　

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    Mast cell tryptases have crucial roles in allergic and inflammatory diseases. The mouse tryptase genes represent a cluster of loci on chromosome 16p3.3. While their functional studies have been extensively performed, transcriptional regulation of tryptase genes is poorly understood. In this study, we examined the molecular basis of the tryptase gene expression in bone marrow-derived mast cells (BMMCs) of C57BL/6 mice and in MEDMC-BRC6 mast cells. The expression of the Tpsb2 and Tpsg1 genes, which reside at the 3'-end of the tryptase locus, is significantly decreased by the reduction of the GATA transcription factors GATA1 or GATA2. Chromatin immunoprecipitation assays have shown that the GATA factors bind at multiple regions within the locus, including 1.0 and 72.8 kb upstream of the Tpsb2 gene, and that GATA1 and GATA2 facilitate each other's DNA binding activity to these regions. Deletion of the -72.8 kb region by genome editing significantly reduced the Tpsb2 and Tpsg1 mRNA levels in MEDMC-BRC6 cells. Furthermore, binding of CTCF and the cohesin subunit Rad21 was found upstream of the -72.8 kb region and was significantly reduced in the absence of GATA1. These results suggest that mouse tryptase gene expression is coordinately regulated by GATA1 and GATA2 in BMMCs.

  27. The Gata2 repression during 3T3-L1 preadipocyte differentiation is dependent on a rapid decrease in histone acetylation in response to glucocorticoid receptor activation. International-journal Peer-reviewed

    Yasushi Ishijima, Shin'ya Ohmori, Ai Uneme, Yusuke Aoki, Miki Kobori, Terutoshi Ohida, Momoko Arai, Misa Hosaka, Kinuko Ohneda

    Molecular and cellular endocrinology　483　39-49　2019/03/01

    DOI： 10.1016/j.mce.2019.01.002 　

    ISSN： 0303-7207

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    The transcription factor GATA2 is an anti-adipogenic factor whose expression is downregulated during adipocyte differentiation. The present study attempted to clarify the molecular mechanism underlying the GATA2 repression and found that the repression is dependent on the activation of the glucocorticoid receptor (GR) during 3T3-L1 preadipocyte differentiation. Although several recognition sequences for GR were found in both the proximal and distal regions of the Gata2 locus, the promoter activity was not affected by the GR activation in the reporter assays, and the CRISPR-Cas9-mediated deletion of the two distal regions of the Gata2 locus was not involved in the GR-mediated Gata2 repression. Notably, the level of histone acetylation was markedly reduced at the Gata2 locus during 3T3-L1 differentiation, and the GR-mediated Gata2 repression was significantly relieved by histone deacetylase inhibition. These results suggest that GR regulates the Gata2 gene by reducing histone acetylation in the early phase of adipogenesis.

  28. Uremic Toxins Affect the Imbalance of Redox State and Overexpression of Prolyl Hydroxylase 2 in Human Adipose Tissue-Derived Mesenchymal Stem Cells Involved in Wound Healing. International-journal Peer-reviewed

    Vuong Cat Khanh, Kinuko Ohneda, Toshiki Kato, Toshiharu Yamashita, Fujio Sato, Kana Tachi, Osamu Ohneda

    Stem cells and development　26　(13)　948-963　2017/07/01

    Publisher: MARY ANN LIEBERT, INC

    DOI： 10.1089/scd.2016.0326 　

    ISSN： 1557-8534

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    Chronic kidney disease (CKD) results in a delay in wound healing because of its complications such as uremia, anemia, and fluid overload. Mesenchymal stem cells (MSCs) are considered to be a candidate for wound healing because of the ability to recruit many types of cells. However, it is still unclear whether the CKD-adipose tissue-derived MSCs (CKD-AT-MSCs) have the same function in wound healing as healthy donor-derived normal AT-MSCs (nAT-MSCs). In this study, we found that uremic toxins induced elevated reactive oxygen species (ROS) expression in nAT-MSCs, resulting in the reduced expression of hypoxia-inducible factor-1α (HIF-1α) under hypoxic conditions. Consistent with the uremic-treated AT-MSCs, there was a definite imbalance of redox state and high expression of ROS in CKD-AT-MSCs isolated from early-stage CKD patients. In addition, a transplantation study clearly revealed that nAT-MSCs promoted the recruitment of inflammatory cells and recovery from ischemia in the mouse flap model, whereas CKD-AT-MSCs had defective functions and the wound healing process was delayed. Of note, the expression of prolyl hydroxylase domain 2 (PHD2) is selectively increased in CKD-AT-MSCs and its inhibition can restore the expression of HIF-1α and the wound healing function of CKD-AT-MSCs. These results indicate that more studies about the functions of MSCs from CKD patients are required before they can be applied in the clinical setting.

  29. Uremic Toxins Affect the Imbalance of Redox State and Overexpression of Prolyl Hydroxylase 2 in Human Adipose Tissue-Derived Mesenchymal Stem Cells Involved in Wound Healing Peer-reviewed

    Vuong Cat Khanh, Kinuko Ohneda, Toshiki Kato, Toshiharu Yamashita, Fujio Sato, Kana Tachi, Osamu Ohneda

    STEM CELLS AND DEVELOPMENT　26　(13)　948-963　2017/07

    DOI： 10.1089/scd.2016.0326 　

    ISSN： 1547-3287

    eISSN： 1557-8534

  30. Microvesicles derived from Alde-Low EPCs support the wound healing capacity of AT-MSCs. International-journal Peer-reviewed

    Tran Cam Tu, Toshiharu Yamashita, Toshiki Kato, Masumi Nagano, Nhu Thuy Trinh, Hiromi Hamada, Fujio Sato, Kinuko Ohneda, Mami Matsuo-Takasaki, Osamu Ohneda

    Biochemical and biophysical research communications　477　(1)　68-75　2016/08/12

    DOI： 10.1016/j.bbrc.2016.06.022 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  31. Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity. International-journal Peer-reviewed

    Nhu-Thuy Trinh, Toshiharu Yamashita, Kinuko Ohneda, Kenichi Kimura, Georgina To'a Salazar, Fujio Sato, Osamu Ohneda

    Stem cells and development　25　(10)　760-73　2016/05/15

    DOI： 10.1089/scd.2015.0335 　

    ISSN： 1547-3287

    eISSN： 1557-8534

  32. Microvesicles enhance the mobility of human diabetic adipose tissue-derived mesenchymal stem cells in vitro and improve wound healing in vivo. International-journal Peer-reviewed

    Nhu Thuy Trinh, Toshiharu Yamashita, Tran Cam Tu, Toshiki Kato, Kinuko Ohneda, Fujio Sato, Osamu Ohneda

    Biochemical and biophysical research communications　473　(4)　1111-1118　2016/05/13

    DOI： 10.1016/j.bbrc.2016.04.025 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  33. A Chemokine Receptor, CXCR4, Which Is Regulated by Hypoxia-Inducible Factor 2α, Is Crucial for Functional Endothelial Progenitor Cells Migration to Ischemic Tissue and Wound Repair. International-journal Peer-reviewed

    Tran Cam Tu, Masumi Nagano, Toshiharu Yamashita, Hiromi Hamada, Kinuko Ohneda, Kenichi Kimura, Osamu Ohneda

    Stem cells and development　25　(3)　266-76　2016/02/01

    DOI： 10.1089/scd.2015.0290 　

    ISSN： 1547-3287

    eISSN： 1557-8534

  34. GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow. International-journal Peer-reviewed

    Shin'ya Ohmori, Takashi Moriguchi, Yuki Noguchi, Muneharu Ikeda, Kota Kobayashi, Nazuki Tomaru, Yasushi Ishijima, Osamu Ohneda, Masayuki Yamamoto, Kinuko Ohneda

    Blood　125　(21)　3306-15　2015/05/21

    DOI： 10.1182/blood-2014-11-612465 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  35. The Human GATA1 Gene Retains a 5' Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts. International-journal Peer-reviewed

    Takashi Moriguchi, Lei Yu, Jun Takai, Makiko Hayashi, Hironori Satoh, Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    Molecular and cellular biology　35　(10)　1825-37　2015/05

    DOI： 10.1128/MCB.00011-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  36. Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression. International-journal Peer-reviewed

    Takashi Moriguchi, Mikiko Suzuki, Lei Yu, Jun Takai, Kinuko Ohneda, Masayuki Yamamoto

    Molecular and cellular biology　35　(5)　805-15　2015/03

    DOI： 10.1128/MCB.01011-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  37. Hypoxia-inducible factor-3α promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene. International-journal Peer-reviewed

    Satomi Kobayashi, Toshiharu Yamashita, Kinuko Ohneda, Masumi Nagano, Kenichi Kimura, Hideto Nakai, Lorenz Poellinger, Osamu Ohneda

    Genes to cells : devoted to molecular & cellular mechanisms　20　(3)　224-41　2015/03

    DOI： 10.1111/gtc.12215 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  38. Transcription factor GATA1 is dispensable for mast cell differentiation in adult mice. International-journal Peer-reviewed

    Kinuko Ohneda, Takashi Moriguchi, Shin'ya Ohmori, Yasushi Ishijima, Hironori Satoh, Sjaak Philipsen, Masayuki Yamamoto

    Molecular and cellular biology　34　(10)　1812-26　2014/05

    DOI： 10.1128/MCB.01524-13 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  39. The Gata1 5' region harbors distinct cis-regulatory modules that direct gene activation in erythroid cells and gene inactivation in HSCs. International-journal Peer-reviewed

    Jun Takai, Takashi Moriguchi, Mikiko Suzuki, Lei Yu, Kinuko Ohneda, Masayuki Yamamoto

    Blood　122　(20)　3450-60　2013/11/14

    DOI： 10.1182/blood-2013-01-476911 　

    ISSN： 0006-4971

  40. GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation. International-journal Peer-reviewed

    Mikiko Suzuki, Maki Kobayashi-Osaki, Shuichi Tsutsumi, Xiaoqing Pan, Shin'ya Ohmori, Jun Takai, Takashi Moriguchi, Osamu Ohneda, Kinuko Ohneda, Ritsuko Shimizu, Yasuharu Kanki, Tatsuhiko Kodama, Hiroyuki Aburatani, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　18　(11)　921-33　2013/11

    DOI： 10.1111/gtc.12086 　

    ISSN： 1356-9597

  41. Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain. International-journal Peer-reviewed

    Harumi Y Mukai, Mikiko Suzuki, Masumi Nagano, Shin'ya Ohmori, Akihito Otsuki, Kouhei Tsuchida, Takashi Moriguchi, Kinuko Ohneda, Ritsuko Shimizu, Osamu Ohneda, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　18　(10)　886-98　2013/10

    Publisher: WILEY-BLACKWELL

    DOI： 10.1111/gtc.12084 　

    ISSN： 1356-9597

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    GATA1 is a transcription factor essential for erythropoiesis and megakaryopoiesis. It has been found that Gata1 gene knockdown heterozygous female (Gata1(G1.05/+)) mice spontaneously develop erythroblastic leukemias. In this study, we have generated a novel Gata1 knockdown erythroblastic cell line, designated GAK14, from the leukemia cells in the Gata1(G1.05/+) mice. Although GAK14 cells maintain immature phenotype on OP9 stromal cells in the presence of erythropoietin and stem cell factor, the cells produce Gr-1-, Mac1-, B220-, CD3e- or CD49b-positive hematopoietic cells when co-cultured with DAS104-8 feeder cells. However, GAK14 cells did not produce erythroid and megakaryocytic lineages, perhaps due to the absence of GATA1. Indeed, GAK14 cells became capable of differentiating into mature erythroid cells when complemented with full-length GATA1 and co-cultured with fetal liver-derived FLS5 stromal cells. This differentiation potential was impaired when GATA1 lacking the N-terminal domain was complemented. The N-terminal domain is known to contribute to the pathogenesis of transient abnormal myelopoiesis and acute megakaryoblastic leukemia related to Down syndrome. These results thus showed that GAK14 cells will serve as a powerful tool for dissecting domain function of GATA1 and that the GATA1 N-terminal domain is essential for the erythroid differentiation of GAK14 cells.

  42. GATA2はマスト細胞の分化形質の維持に必須である

    大森 慎也, 石嶋 康史, 森口 尚, 山本 雅之, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　86回　1T14a-08　2013/09

    Publisher: (公社)日本生化学会

  43. Ablation of Mina53 in mice reduces allergic response in the airways. Peer-reviewed

    Tetsuya Mori, Kengo Okamoto, Yuji Tanaka, Kwesi Teye, Toshiyuki Umata, Kinuko Ohneda, Kenichi Tokuyama, Masaru Okabe, Makoto Tsuneoka

    Cell structure and function　38　(2)　155-67　2013

    eISSN： 1347-3700

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    The mina53 (myc-induced nuclear antigen with a 53 kDa molecular mass; also known as mina) was identified as a direct transcriptional target of the oncoprotein Myc and encodes a conserved protein in vertebrates. While Mina53 is known to be associated with tumorigenesis, it is not clear what role Mina53 plays in non-neoplastic tissues. To directly address the roles of Mina53 in non-neoplastic tissues, we created mina53-deficient mice. Both male and female mina53-deficient mice reached adulthood and were fertile, suggesting that Mina53 is dispensable for the basic developmental processes. Since we found that Mina53 was expressed in cells responsible for immune responses, we investigated whether Mina53 was involved in immune responses. When mice were exposed intranasally to house dust mites as an allergen, the airway tract showed hyperresponsiveness to methacholine in wild-type mice but not in mina53-deficient mice. The mina53-deficient mice also showed a significantly reduced migration of immune cells, including eosinophils, into bronchoalveolar lavage fluid compared with wild-type mice. The levels of Th2 cytokines, IL-4 and IL-5, produced in response to house dust mites were lower in the mina53-deficient mice than in wild-type mice. The level of IFN-γ in bronchoalveolar lavage fluid was significantly decreased by exposure to house dust mites in wild-type mice but not in the mina53-deficient mice. These results suggest that Mina53 plays a role in the allergic response to inhaled allergens, possibly through controlling IL-4 production.

  44. Mast cell deficiency results in the accumulation of preadipocytes in adipose tissue in both obese and non-obese mice. International-journal Peer-reviewed

    Yasushi Ishijima, Shin'ya Ohmori, Kinuko Ohneda

    FEBS open bio　4　18-24　2013

    DOI： 10.1016/j.fob.2013.11.004 　

    ISSN： 2211-5463

  45. Regulation of GATA factor expression is distinct between erythroid and mast cell lineages. International-journal Peer-reviewed

    Shin'ya Ohmori, Jun Takai, Yasushi Ishijima, Mikiko Suzuki, Takashi Moriguchi, Sjaak Philipsen, Masayuki Yamamoto, Kinuko Ohneda

    Molecular and cellular biology　32　(23)　4742-55　2012/12

    DOI： 10.1128/MCB.00718-12 　

    ISSN： 0270-7306

  46. GATA transcription factors are involved in IgE-dependent mast cell degranulation by enhancing the expression of phospholipase C-γ1. International-journal Peer-reviewed

    Yasushi Ishijima, Shin'ya Ohmori, Ayano Uenishi, Kinuko Ohneda

    Genes to cells : devoted to molecular & cellular mechanisms　17　(4)　285-301　2012/04

    DOI： 10.1111/j.1365-2443.2012.01588.x 　

    ISSN： 1356-9597

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    Mast cell degranulation is a dynamic, highly organized process involving numerous signaling molecules and enzymes. Although the molecular mechanisms underlying antigen-mediated mast cell degranulation have been studied intensively, little is known about the transcriptional control of this process. Here, we show that the hematopoietic transcription factors GATA1 and GATA2 are involved in mast cell degranulation through the control of phospholipase C-γ1 (PLC-γ1) expression. Knockdown of GATA1 and/or GATA2 by specific siRNA significantly reduced antigen-induced degranulation and Ca(2+) mobilization in the rat basophilic leukemia cell line RBL-2H3. RT-PCR analyses showed that PLC-γ1 expression was significantly decreased by this GATA factor repression. Other GATA factor targets, such as the previously reported α and β subunits of the high-affinity IgE receptor (FcεRI), were unaffected. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that GATA factors directly activate PLC-γ1 gene transcription through a conserved GATA-binding motif that resides in the 5'-upstream sequence. Furthermore, we show evidence that the PLC-γ1 expression is regulated by GATA2 in mast cells derived from mouse bone marrow. These data indicate that PLC-γ1 is a target gene of GATA factors in mast cells and provide evidence that GATA1 and GATA2 control antigen-mediated mast cell degranulation by regulating the expression of PLC-γ1.

  47. Identification of human placenta-derived mesenchymal stem cells involved in re-endothelialization. International-journal Peer-reviewed

    Tu Cam Tran, Kenichi Kimura, Masumi Nagano, Toshiharu Yamashita, Kinuko Ohneda, Haruhiko Sugimori, Fujio Sato, Yuzuru Sakakibara, Hiromi Hamada, Hiroyuki Yoshikawa, Son Nghia Hoang, Osamu Ohneda

    Journal of cellular physiology　226　(1)　224-35　2011/01

    DOI： 10.1002/jcp.22329 　

    ISSN： 0021-9541

    eISSN： 1097-4652

  48. Hypoxia responsive mesenchymal stem cells derived from human umbilical cord blood are effective for bone repair. International-journal Peer-reviewed

    Masumi Nagano, Kenichi Kimura, Toshiharu Yamashita, Kinuko Ohneda, Daisuke Nozawa, Hiromi Hamada, Hiroyuki Yoshikawa, Naoyuki Ochiai, Osamu Ohneda

    Stem cells and development　19　(8)　1195-210　2010/08

    Publisher: MARY ANN LIEBERT INC

    DOI： 10.1089/scd.2009.0447 　

    ISSN： 1547-3287

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    Mesenchymal stem cells (MSCs) are highly useful in a variety of cell therapies owing to their multipotential differentiation capability. MSCs derived from umbilical cord blood are generally isolated by their plastic adherence without using specific cell surface markers and examined for their osteogenic, adipogenic, and chondrogenic differentiation properties retrospectively. Here, we report 2 subpopulations of MSCs, separated based on aldehyde dehydrogenase (ALDH) activity. MSCs with a high ALDH activity (Alde-High) proliferated more than those with a low ALDH activity (Alde-Low). Alde-High MSCs had a greater ability to differentiate than Alde-Low MSCs in in vitro culture. Transplantation of Alde-High MSCs into fractured mouse femurs enabled early repair of tissues and rapid bone substitution. Alde-High MSCs were also more responsive to hypoxia than Alde-Low MSCs, with the upregulation of Flt-1, CXCR4, and Angiopoietin-2. Thus, MSCs with a high ALDH activity might serve as an effective therapeutic tool for healing fractures within a short period of time.

  49. Fractionation of mature eosinophils in GATA-reporter transgenic mice. Peer-reviewed

    Kibom Kim, Norio Suzuki, Kinuko Ohneda, Naoko Minegishi, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　220　(2)　127-38　2010/02

    DOI： 10.1620/tjem.220.127 　

    eISSN： 1349-3329

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    Eosinophils contribute to the pathophysiology of allergic and infectious diseases, albeit their molecular functions remain unknown. Mature eosinophils are identified by their unique morphology and staining characteristics. However, it is difficult to fractionate living eosinophils by flow cytometry because these granulocytes express multiple cell surface markers that are shared by other cells of hematopoietic or non-hematopoietic origin. In this study, we describe a flow cytometry-based method to enumerate and fractionate eosinophils by developmental stages. To fractionate these cell types, we used transgenic mouse lines that express fluorescent proteins under control of the Gata1 gene hematopoietic regulatory region (Gata1-HRD), which is exclusively active in Gata1-expressing hematopoietic cells, including eosinophils. As expected, mature eosinophils were highly enriched in the fluorescent reporter-expressing subfraction of bone marrow myeloid cells that were negatively selected by using multiple antibodies against B220, CD4, CD8, Ter119, c-Kit and CD71. Cytochemical analyses of flow-sorted cells identified the cells in this fraction as eosinophils harboring eosinophilic granules. Additionally, expression of eosinophil-specific genes, for instance eosinophil enzymes and the IL-5 receptor alpha gene, were specifically detected in this fraction. The expression of these eosinophil-specific genes increased as the cells differentiated. This method for enrichment of bone marrow eosinophils is applicable to fractionation of eosinophils and bronchoalveolar lavage fluid from transgenic mice with atopic asthma. Thus, both pathological and developmental stages of eosinophils are efficiently fractionated by this flow cytometry-based method using Gata1-HRD transgenic reporter mice. This study, therefore, proposes a useful means to study the experimental allergic and inflammatory systems.

  50. Characterization of a functional ZBP-89 binding site that mediates Gata1 gene expression during hematopoietic development. International-journal Peer-reviewed

    Kinuko Ohneda, Shin'ya Ohmori, Yasushi Ishijima, Mayu Nakano, Masayuki Yamamoto

    The Journal of biological chemistry　284　(44)　30187-99　2009/10/30

    DOI： 10.1074/jbc.M109.026948 　

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    GATA-1 is a lineage-restricted transcription factor that plays essential roles in hematopoietic development. The Gata1 gene hematopoietic enhancer allowed Gata1 reporter expression in erythroid cells and megakaryocytes of transgenic mice. The Gata1 hematopoietic enhancer activity is strictly dependent on a GATA site located in the 5' region of the enhancer. However, the importance of the GC-rich region adjacent to the 3'-end of this GATA site has been also suggested. In this study, we show that this GC-rich region contains five contiguous deoxyguanosine residues (G(5) string) that are bound by multiple nuclear proteins. Interestingly, deletion of one deoxyguanosine residue from the G(5) string (G(4) mutant) specifically eliminates binding to ZBP-89, a Krüppel-like transcription factor, but not to Sp3 and other binding factors. We demonstrate that GATA-1 and ZBP-89 occupy chromatin regions of the Gata1 enhancer and physically associate in vitro through zinc finger domains. Gel mobility shift assays and DNA affinity precipitation assays suggest that binding of ZBP-89 to this region is reduced in the absence of GATA-1 binding to the G1HE. Luciferase reporter assays demonstrate that ZBP-89 activates the Gata1 enhancer depending on the G(5) string sequence. Finally, transgenic mouse studies reveal that the G(4) mutation significantly reduced the reporter activity of the Gata1 hematopoietic regulatory domain encompassing an 8.5-kbp region of the Gata1 gene. These data provide compelling evidence that the G(5) string is necessary for Gata1 gene expression in vivo and ZBP-89 is the functional trans-acting factor for this cis-acting region.

  51. Differential contribution of the Gata1 gene hematopoietic enhancer to erythroid differentiation. International-journal Peer-reviewed

    Mikiko Suzuki, Takashi Moriguchi, Kinuko Ohneda, Masayuki Yamamoto

    Molecular and cellular biology　29　(5)　1163-75　2009/03

    DOI： 10.1128/MCB.01572-08 　

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    GATA1 is a key regulator of erythroid cell differentiation. To examine how Gata1 gene expression is regulated in a stage-specific manner, transgenic mouse lines expressing green fluorescent protein (GFP) reporter from the Gata1 locus in a bacterial artificial chromosome (G1BAC-GFP) were prepared. We found that the GFP reporter expression faithfully recapitulated Gata1 gene expression. Using GFP fluorescence in combination with hematopoietic surface markers, we established a purification protocol for two erythroid progenitor fractions, referred to as burst-forming units-erythroid cell-related erythroid progenitor (BREP) and CFU-erythroid cell-related erythroid progenitor (CREP) fractions. We examined the functions of the Gata1 gene hematopoietic enhancer (G1HE) and the highly conserved GATA box in the enhancer core. Both deletion of the G1HE and substitution mutation of the GATA box caused almost complete loss of GFP expression in the BREP fraction, but the CREP stage expression was suppressed only partially, indicating the critical contribution of the GATA box to the BREP stage expression of Gata1. Consistently, targeted deletion of G1HE from the chromosomal Gata1 locus provoked suppressed expression of the Gata1 gene in the BREP fraction, which led to aberrant accumulation of BREP stage hematopoietic progenitor cells. These results demonstrate the physiological significance of the dynamic regulation of Gata1 gene expression in a differentiation stage-specific manner.

  52. A Chemokine Receptor CXCR4 Plays a Crucial Role for Repairing Ischemic Tissue through Regulation of HIF-2a Peer-reviewed

    Nagano, Masumi, Kimura, Ken-ichi, Yamashita, Toshiharu, Hamada, Hiromi, Ohneda, Kinuko, Yoshikawa, Hiroyuki, Ohneda, Osamu

    BLOOD　112　(11)　1336-1337　2008/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  53. The microenvironment for erythropoiesis is regulated by HIF-2alpha through VCAM-1 in endothelial cells. International-journal Peer-reviewed

    Toshiharu Yamashita, Osamu Ohneda, Ai Sakiyama, Fumiko Iwata, Kinuko Ohneda, Yoshiaki Fujii-Kuriyama

    Blood　112　(4)　1482-92　2008/08/15

    Publisher: AMER SOC HEMATOLOGY

    DOI： 10.1182/blood-2007-11-122648 　

    ISSN： 0006-4971

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    Erythropoiesis is a dynamic process regulated by oxygen in vertebrates. Recent evidence has indicated that erythropoietin (Epo) expression is regulated by hypoxia-inducible transcription factors (HIFs), HIF-2alpha in particular. In this study, we report that knockdown mutation of HIF-2alpha in mice (kd/kd) results in normocytic anemia, despite Epo induction in response to hypoxia not being severely affected. Transplantation analyses clearly demonstrated that the hematopoietic microenvironment, but not the hematopoietic cells, was altered in kd/kd. Furthermore, cell-type specific recovery of HIF-2alpha expression in endothelial cells (ECs) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2alpha in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2alpha, the expression of vascular adhesion molecule-1 (VCAM-1) was reduced significantly and restoration of VCAM-1 expression in kd/kd ECs enhanced the development of erythroid progenitors. Finally, a chromatin immunoprecipitation assay and a reporter assay indicated that VCAM-1 gene transcription is directly regulated by HIF-2alpha. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2alpha in ECs.

  54. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. International-journal Peer-reviewed

    Toshiharu Yamashita, Kinuko Ohneda, Masumi Nagano, Chika Miyoshi, Naomi Kaneko, Yoshihiro Miwa, Masayuki Yamamoto, Osamu Ohneda, Yoshiaki Fujii-Kuriyama

    The Journal of biological chemistry　283　(27)　18926-36　2008/07/04

    Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI： 10.1074/jbc.M709133200 　

    ISSN： 0021-9258

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    The hypoxia-inducible transcription factors (HIF)-1alpha and -2alpha mediate responses to hypoxia, such as tumor neovascularization. To determine the function of HIF-2alpha in vascular endothelial cells (ECs), we examined vascular formation in HIF-2alpha knockdown (kd/kd) mice transplanted with tumors. We observed that both the tumor size and the number of large vessels growing within transplanted melanomas were significantly reduced in kd/kd recipients compared with wild-type (WT) mice. In contrast, we observed a similar extent of vascular formation within fibrosarcomas transplanted from either kd/kd or WT mice into WT recipients. Thus, HIF-2alpha expression in host animal ECs, but not in the tumor cells, is crucial for tumor neovascularization. HIF-2alpha may function through ephrin A1 as the expression of ephrin A1 and related genes was markedly reduced in kd/kd ECs, and HIF-2alpha specifically bound a hypoxia-response element sequence in the ephrin A1 promoter. Treatment of WT ECs with an ephrin A1 inhibitor (ephrin A1-Fc) also impaired neovascularization. We conclude that in ECs, HIF-2alpha plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1.

  55. Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis. International-journal Peer-reviewed

    Laura Gutiérrez, Saho Tsukamoto, Mikiko Suzuki, Harumi Yamamoto-Mukai, Masayuki Yamamoto, Sjaak Philipsen, Kinuko Ohneda

    Blood　111　(8)　4375-85　2008/04/15

    DOI： 10.1182/blood-2007-09-115121 　

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    The transcription factor Gata1 is expressed in several hematopoietic lineages and plays essential roles in normal hematopoietic development during embryonic stages. The lethality of Gata1-null embryos has precluded determination of its role in adult erythropoiesis. Here we have examined the effects of Gata1 loss in adult erythropoiesis using conditional Gata1 knockout mice expressing either interferon- or tamoxifen-inducible Cre recombinase (Mx-Cre and Tx-Cre, respectively). Mx-Cre-mediated Gata1 recombination, although incomplete, resulted in maturation arrest of Gata1-null erythroid cells at the proerythroblast stage, thrombocytopenia, and excessive proliferation of megakaryocytes in the spleen. Tx-Cre-mediated Gata1 recombination resulted in depletion of the erythroid compartment in bone marrow and spleen. Formation of the early and late erythroid progenitors in bone marrow was significantly reduced in the absence of Gata1. Furthermore, on treatment with a hemolytic agent, these mice failed to activate a stress erythropoietic response, despite the rising erythropoietin levels. These results indicate that, in addition to the requirement of Gata1 in adult megakaryopoiesis, Gata1 is necessary for steady-state erythropoiesis and for erythroid expansion in response to anemia. Thus, ablation of Gata1 in adult mice results in a condition resembling aplastic crisis in human.

  56. Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS. International-journal Peer-reviewed

    Toshiharu Yamashita, Osamu Ohneda, Masumi Nagano, Motoyuki Iemitsu, Yuichi Makino, Hirotoshi Tanaka, Takashi Miyauchi, Katsutoshi Goto, Kinuko Ohneda, Yoshiaki Fujii-Kuriyama, Lorenz Poellinger, Masayuki Yamamoto

    Molecular and cellular biology　28　(4)　1285-97　2008/02

    DOI： 10.1128/MCB.01332-07 　

    eISSN： 1098-5549

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    Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3alpha gene by alternative splicing, replacing the first exon of HIF-3alpha with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3alpha. NEPAS suppressed reporter gene expression driven by HIF-1alpha and HIF-2alpha. By generating mice with a targeted disruption of the NEPAS/HIF-3alpha locus, we found that homozygous mutant mice (NEPAS/HIF-3alpha(-)(/)(-)) were viable but displayed enlargement of the right ventricle and impaired lung remodeling. The expression of endothelin 1 and platelet-derived growth factor beta was increased in the lung endothelial cells of NEPAS/HIF-3alpha-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1alpha and HIF-2alpha are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.

  57. Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood. International-journal Peer-reviewed

    Masumi Nagano, Toshiharu Yamashita, Hiromi Hamada, Kinuko Ohneda, Ken-ichi Kimura, Tomoki Nakagawa, Masabumi Shibuya, Hiroyuki Yoshikawa, Osamu Ohneda

    Blood　110　(1)　151-60　2007/07/01

    Publisher: AMER SOC HEMATOLOGY

    DOI： 10.1182/blood-2006-10-047092 　

    ISSN： 0006-4971

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    Umbilical cord blood (UCB) has been used as a potential source of various kinds of stem cells, including hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells (EPCs), for a variety of cell therapies. Recently, EPCs were introduced for restoring vascularization in ischemic tissues. An appropriate procedure for isolating EPCs from UCB is a key issue for improving therapeutic efficacy and eliminating the unexpected expansion of nonessential cells. Here we report a novel method for isolating EPCs from UCB by a combination of negative immunoselection and cell culture techniques. In addition, we divided EPCs into 2 subpopulations according to the aldehyde dehydrogenase (ALDH) activity. We found that EPCs with low ALDH activity (Alde-Low) possess a greater ability to proliferate and migrate compared to those with high ALDH activity (Alde-High). Moreover, hypoxia-inducible factor proteins are up-regulated and VEGF, CXCR4, and GLUT-1 mRNAs are increased in Alde-Low EPCs under hypoxic conditions, while the response was not significant in Alde-High EPCs. In fact, the introduction of Alde-Low EPCs significantly reduced tissue damage in ischemia in a mouse flap model. Thus, the introduction of Alde-Low EPCs may be a potential strategy for inducing rapid neovascularization and subsequent regeneration of ischemic tissues.

  58. Dynamic regulation of Gata factor levels is more important than their identity. International-journal Peer-reviewed

    Rita Ferreira, Albert Wai, Ritsuko Shimizu, Nynke Gillemans, Robbert Rottier, Marieke von Lindern, Kinuko Ohneda, Frank Grosveld, Masayuki Yamamoto, Sjaak Philipsen

    Blood　109　(12)　5481-90　2007/06/15

    DOI： 10.1182/blood-2006-11-060491 　

    ISSN： 0006-4971

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    Three Gata transcription factors (Gata1, -2, and -3) are essential for hematopoiesis. These factors are thought to play distinct roles because they do not functionally replace each other. For instance, Gata2 messenger RNA (mRNA) expression is highly elevated in Gata1-null erythroid cells, yet this does not rescue the defect. Here, we test whether Gata2 and -3 transgenes rescue the erythroid defect of Gata1-null mice, if expressed in the appropriate spatiotemporal pattern. Gata1, -2, and -3 transgenes driven by beta-globin regulatory elements, directing expression to late stages of differentiation, fail to rescue erythropoiesis in Gata1-null mutants. In contrast, when controlled by Gata1 regulatory elements, directing expression to the early stages of differentiation, Gata1, -2, and -3 do rescue the Gata1-null phenotype. The dramatic increase of endogenous Gata2 mRNA in Gata1-null progenitors is not reflected in Gata2 protein levels, invoking translational regulation. Our data show that the dynamic spatiotemporal regulation of Gata factor levels is more important than their identity and provide a paradigm for developmental control mechanisms that are hard-wired in cis-regulatory elements.

  59. GATA-1 self-association controls erythroid development in vivo. International-journal Peer-reviewed

    Ritsuko Shimizu, Cecelia D Trainor, Keizo Nishikawa, Makoto Kobayashi, Kinuko Ohneda, Masayuki Yamamoto

    The Journal of biological chemistry　282　(21)　15862-71　2007/05/25

    DOI： 10.1074/jbc.M701936200 　

    ISSN： 0021-9258

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    GATA-1 is the key transcription factor for the development of the erythroid, megakaryocytic, eosinophilic, and mast cell lineages. GATA-1 possesses the ability to self-associate, and this characteristic has been suggested to be important for GATA-1 function. To elucidate the roles self-associated GATA-1 plays during hematopoietic cell development in vivo, in this study we prepared GATA-1 mutants in which three lysine residues potentially contributing to the self-association (Lys-245, Lys-246, and Lys-312) are substituted in combination with alanines. Of the mutants, 3KA harboring alanine substitutions in all three lysines showed reduced self-association activity without considerable interference in the modification of GATA-1 by acetylation. We generated transgenic mouse lines that express these GATA-1 mutants utilizing the Gata1 hematopoietic regulatory domain, and crossed the mice to Gata1 knockdown (GATA-1.05) mutant mice. Although NKA (K245A and K246A) and CKA (K312A) mutants almost fully rescued the GATA-1.05 mice from anemia and embryonic lethality, the 3KA mutant only partially rescued the GATA-1.05 mutant mice. Even with the higher than endogenous level expression, GATA-1.05/Y::3KA embryos were prone to die at various stages in mid-to-late gestation. Live birth and an anemic phenotype were restored in some embryos depending on the expression level of the 3KA transgene. The expression of the transferrin receptor and heme biosynthesis enzymes was impaired in the yolk sac and liver of the 3KA-rescued embryos. Immature erythroid cells with insufficient expression of the transferrin receptor accumulated in the livers of 3KA-rescued embryos. These results provide the first convincing line of evidence that the self-association of GATA-1 is important for proper mammalian erythroid development in vivo.

  60. GATA-4 incompletely substitutes for GATA-1 in promoting both primitive and definitive erythropoiesis in vivo. International-journal Peer-reviewed

    Sakie Hosoya-Ohmura, Naomi Mochizuki, Mikiko Suzuki, Osamu Ohneda, Kinuko Ohneda, Masayuki Yamamoto

    The Journal of biological chemistry　281　(43)　32820-30　2006/10/27

    DOI： 10.1074/jbc.M605735200 　

    ISSN： 0021-9258

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    Vertebrate GATA transcription factors have been classified into two subgroups; GATA-1, GATA-2, and GATA-3 are expressed in hematopoietic cells, whereas GATA-4, GATA-5, and GATA-6 are expressed in mesoendoderm-derived tissues. We previously discovered that expression of GATA-2 or GATA-3 under the transcriptional control for the Gata1 gene eliminates lethal anemia in Gata1 germ line mutant mice (Gata1.05/Y). Here, we show that the GATA-4 expression by the same regulatory cassette prolongs the life span of Gata1.05/Y embryos from embryonic day 12.5 to 15.5 but fails to abrogate its embryonic lethality. Gata1.05/Y mice bearing the GATA-4 transgene showed impaired maturation of both primitive and definitive erythroid cells and defective erythroid cell expansion in fetal liver. Moreover, the incidence of apoptosis was observed prominently in primitive erythroid cells. In contrast, a GATA-4-GATA-1 chimeric protein prepared by linking the N-terminal region of GATA-4 to the C-terminal region of GATA-1 significantly promoted the differentiation and survival of primitive erythroid cells, although this protein is still insufficient for rescuing Gata1.05/Y embryos from lethal anemia. These data thus show a functional incompatibility between hematopoietic and endodermal GATA factors in vivo and provide evidence indicating specific roles of the C-terminal region of GATA-1 in primitive erythropoiesis.

  61. Real-time monitoring of stress erythropoiesis in vivo using Gata1 and beta-globin LCR luciferase transgenic mice. International-journal Peer-reviewed

    Mikiko Suzuki, Kinuko Ohneda, Sakie Hosoya-Ohmura, Saho Tsukamoto, Osamu Ohneda, Sjaak Philipsen, Masayuki Yamamoto

    Blood　108　(2)　726-33　2006/07/15

    DOI： 10.1182/blood-2005-10-4064 　

    ISSN： 0006-4971

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    Erythroid progenitors have the potential to proliferate rapidly in response to environmental stimuli. This process is referred to as stress erythropoiesis, with erythropoietin (EPO) playing central roles in its promotion. In this study, we wanted to elucidate the molecular mechanisms governing the regulation of stress erythropoiesis and the maintenance of red-cell homeostasis. This was achieved by our development of a noninvasive real-time monitoring system for erythropoiesis using transgenic mouse lines expressing luciferase under the control of the mouse Gata1 hematopoietic regulatory domain (G1-HRD-luc) or human beta-globin locus control region (Hbb-LCR-luc). Optical bioluminescence images revealed that the luciferase was specifically expressed in spleen and bone marrow and was induced rapidly in response to anemia and hypoxia stimuli. The G1-HRD-luc activity tracked the emergence and disappearance of proerythroblast-stage progenitors, whereas the Hbb-LCR-luc activity tracked erythroblasts and later stage erythroid cells. Increased plasma EPO concentration preceded an increase in G1-HRD-luc, supporting our contention that EPO acts as the key upstream signal in stress erythropoiesis. Hence, we conclude that G1-HRD-luc and Hbb-LCR-luc reporters are differentially activated during stress erythropoiesis and that the transgenic mouse lines used serve as an important means for understanding the homeostatic regulation of erythropoiesis.

  62. Graded levels of GATA-1 expression modulate survival, proliferation, and differentiation of erythroid progenitors. International-journal Peer-reviewed

    Xiaoqing Pan, Osamu Ohneda, Kinuko Ohneda, Fokke Lindeboom, Fumiko Iwata, Ritsuko Shimizu, Masumi Nagano, Naruyoshi Suwabe, Sjaak Philipsen, Kim-Chew Lim, James D Engel, Masayuki Yamamoto

    The Journal of biological chemistry　280　(23)　22385-94　2005/06/10

    DOI： 10.1074/jbc.M500081200 　

    ISSN： 0021-9258

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    Transcription factor GATA-1 plays an important role in gene regulation during the development of erythroid cells. Several reports suggest that GATA-1 plays multiple roles in survival, proliferation, and differentiation of erythroid cells. However, little is known about the relationship between the level of GATA-1 expression and its nature of multifunction to affect erythroid cell fate. To address this issue, we developed in vitro embryonic stem (ES) culture system by using OP9 stromal cells (OP9/ES cell co-culture system), and cultured the mutant (GATA-1.05 and GATA-1-null) and wild type (WT)ES cells, respectively. By using this OP9/ES cell co-culture system, primitive and definitive erythroid cells were developed individually, and we examined how expression level of GATA-1 affects the development of erythroid cells. GATA-1.05 ES-derived definitive erythroid cells were immature with the appearance of proerythroblasts, and highly proliferated, compared with WT and GATA-1-null ES-derived erythroid cells. Extensive studies of cell cycle kinetics revealed that the GATA-1.05 proerythroblasts accumulated in S phase and expressed lower levels of p16(INK4A) than WT ES cell-derived proerythroblasts. We concluded that GATA-1 must achieve a critical threshold activity to achieve selective activation of specific target genes, thereby influencing the developmental decision of an erythroid progenitor cell to undergo apoptosis, proliferation, or terminal differentiation.

  63. [Flies, fishes and frogs turn the tide of hematopoietic research]. Peer-reviewed

    Kinuko Ohneda, Masayuki Yamamoto

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　50　(6 Suppl)　633-7　2005/05

    ISSN： 0039-9450

  64. Essential role of synoviolin in embryogenesis. International-journal Peer-reviewed

    Naoko Yagishita, Kinuko Ohneda, Tetsuya Amano, Satoshi Yamasaki, Akiko Sugiura, Kaneyuki Tsuchimochi, Hiroshi Shin, Ko-Ichi Kawahara, Osamu Ohneda, Tomohiko Ohta, Sakae Tanaka, Masayuki Yamamoto, Ikuro Maruyama, Kusuki Nishioka, Akiyoshi Fukamizu, Toshihiro Nakajima

    The Journal of biological chemistry　280　(9)　7909-16　2005/03/04

    DOI： 10.1074/jbc.M410863200 　

    ISSN： 0021-9258

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    We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno(-/-)) mice by genetargeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno(-/-) fetal liver. Moreover, definitive erythropoiesis was affected in non-cell autonomous manner in syno(-/-) embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno(-/-) mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno(+/+) mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.

  65. Essential role of synoviolin in embryonic hematopoiesis. Peer-reviewed

    Yagishita, N, Amano, T, Yamasaki, S, Tsuchimochi, K, Shin, H, Kawahara, K, Ohneda, K, Ohneda, O, Yamamoto, M, Nishioka, K, Maruyama, I, Fukamizu, A.Nakajima T

    Journal of Biological Chemistry　(280)　7909 7916　2005/01

  66. Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells. International-journal Peer-reviewed

    Mayu Nakano, Kinuko Ohneda, Harumi Yamamoto-Mukai, Ritsuko Shimizu, Osamu Ohneda, Sakie Ohmura, Mikiko Suzuki, Saho Tsukamoto, Toru Yanagawa, Hiroshi Yoshida, Yuichi Takakuwa, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　10　(1)　47-62　2005/01

    DOI： 10.1111/j.1365-2443.2005.00814.x 　

    ISSN： 1356-9597

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    Transcription factor GATA-1 is essential for erythroid cell differentiation. GATA-binding motifs have been found in the regulatory regions of various erythroid-specific genes, suggesting that GATA-1 contributes to gene regulation during the entire process of erythropoiesis. A GATA-1 germ-line mutation results in embryonic lethality due to defective primitive erythropoiesis and GATA-1-null embryonic stem cells fails to differentiate beyond the proerythroblast stage. Therefore, the precise roles of GATA-1 in the later stages of erythropoiesis could not be clarified. Under the control of a GATA-1 gene hematopoietic regulatory domain, a GATA-1 mutant lacking the N-finger domain (DeltaNF mutant) was over-expressed in mice. These mice exhibited abnormal morphology in peripheral red blood cells (RBCs), reticulocytosis, splenomegaly, and erythroid hyperplasia, indicating compensated hemolysis. These mice were extremely sensitive to phenylhydrazine (PHZ), an agent that induces hemolysis, and their RBCs were osmotically fragile. Importantly, the hemolytic response to PHZ was partially restored by the simultaneous expression of wild-type GATA-1 with the DeltaNF mutant, supporting our contention that DeltaNF protein competitively inhibits the function of endogenous GATA-1. These data provide the first in vivo evidence that the NF domain contributes to the gene regulation that is critical for differentiation and survival of mature RBCs in postnatal erythropoiesis.

  67. Leukemogenesis caused by incapacitated GATA-1 function. International-journal Peer-reviewed

    Ritsuko Shimizu, Takashi Kuroha, Osamu Ohneda, Xiaoqing Pan, Kinuko Ohneda, Satoru Takahashi, Sjaak Philipsen, Masayuki Yamamoto

    Molecular and cellular biology　24　(24)　10814-25　2004/12

    DOI： 10.1128/MCB.24.24.10814-10825.2004 　

    ISSN： 0270-7306

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    GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.

  68. Transgenic rescue of GATA-1 deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia Invited Peer-reviewed

    SHIMIZU R

    Blood　103　(7)　2560-2567　2004/04/01

    DOI： 10.1182/blood-2003-07-2514 　

  69. GATA-1 testis activation region is essential for Sertoli cell-specific expression of GATA-1 gene in transgenic mouse Invited Peer-reviewed

    WAKABAYASHI J.

    Genes Cells　8　(7)　619-630　2003/07

    DOI： 10.1046/j.1365-2443.2003.00658.x 　

  70. A minigene containing four discrete cis elements recapitulates GATA-1 gene expression in vivo Peer-reviewed

    OHNEDA K.

    Genes Cells　7　(12)　1243-1254　2002/12

    DOI： 10.1046/j.1365-2443.2002.00595.x 　

  71. Reduction of spontaneous and irradiation-induced apoptosis in small intestine of IGF-I transgenic mice. International-journal Peer-reviewed

    Heather R Wilkins, Kinuko Ohneda, Temitope O Keku, A Joseph D'Ercole, C Randall Fuller, Kristen L Williams, P Kay Lund

    American journal of physiology. Gastrointestinal and liver physiology　283　(2)　G457-64-G464　2002/08

    DOI： 10.1152/ajpgi.00019.2002 　

    ISSN： 0193-1857

  72. Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage Peer-reviewed

    K Ohneda, M Yamamoto

    ACTA HAEMATOLOGICA　108　(4)　237-245　2002

    DOI： 10.1159/000065660 　

    ISSN： 0001-5792

  73. ALCAM (CD166): its role in hematopoietic and endothelial development Peer-reviewed

    O Ohneda, K Ohneda, F Arai, J Lee, T Miyamoto, Y Fukushima, D Dowbenko, LA Lasky, T Suda

    BLOOD　98　(7)　2134-2142　2001/10

    ISSN： 0006-4971

  74. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis Peer-reviewed

    SHIMIZU R.

    EMBO J.　20　(18)　5250-5260　2001/09/17

    DOI： 10.1093/emboj/20.18.5250 　

  75. 成体での血管新生におけるHLFの役割

    守田 匡伸, 高橋 智, 中島 修, 大根田 絹子, 山下 年晴, 依馬 正次, 柴原 茂樹, 鵜殿 徹男, 富田 浩史, 玉井 信

    生化学　73　(8)　918-918　2001/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  76. The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter Peer-reviewed

    K Ohneda, RG Mirmira, JH Wang, JD Johnson, MS German

    MOLECULAR AND CELLULAR BIOLOGY　20　(3)　900-911　2000/02

    ISSN： 0270-7306

  77. WECHE: A novel hematopoietic regulatory factor

    O Ohneda, K Ohneda, H Nomiyama, Z Zheng, SA Gold, F Arai, T Miyamoto, BE Taillon, RA McIndoe, RA Shimkets, DA Lewin, T Suda, LA Lasky

    IMMUNITY　12　(2)　141-150　2000/02

    ISSN： 1074-7613

  78. WECHE: A novel hematopoietic regulatory factor

    Osamu Ohneda, Kinuko Ohneda, Hisayuki Nomiyama, Zhong Zheng, Steven A. Gold, Fumio Arai, Takeshi Miyamoto, Bruce E. Taillon, Richard A. McIndoe, Richard A. Shimkets, David A. Lewin, Toshio Suda, Laurence A. Lasky

    Journal of Cultural Heritage　1　141-150　2000/01/01

    ISSN： 1296-2074

Show all ︎Show first 5

Misc. 46

  1. 一般住民コホート参加者に対する遺伝性乳がん卵巣がんの遺伝情報回付事業

    湊 純子, 島田 宗昭, 栃木 実佳子, 大根田 絹子, 濱中 洋平, 宮原 周子, 渋谷 祐介, 橋本 千明, 石橋 ますみ, 重田 昌吾, 徳永 英樹

    日本婦人科腫瘍学会学術講演会プログラム・抄録集　66回　332-332　2024/07

    Publisher: (公社)日本婦人科腫瘍学会

  2. ゲノム医療におけるバイオバンクの役割とその利活用 7.バイオバンクの産学連携による利活用促進

    大根田絹子, 野口憲一

    遺伝子医学　14　(1)　2024

    ISSN： 1343-0971

  3. 未発症のBRCA1/2病的バリアント保持者に対するサーベイランスの課題

    濱中 洋平, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 本成 登貴和, 川目 裕, 鈴木 洋一, 長神 風二, 布施 昇男, 大根田 絹子, 山本 雅之, 石田 孝宣

    日本乳癌検診学会学術総会プログラム抄録集　33回　148-148　2023/11

    Publisher: (NPO)日本乳癌検診学会

  4. 転写因子GATA2は炎症関連遺伝子座のクロマチン構造を変換し発現活性化に寄与する

    高井 淳, 植木 陽向, 大森 慎也, 大根田 絹子, 上村 聡志, 森口 尚

    日本生化学会大会プログラム・講演要旨集　96回　[2P-407]　2023/10

    Publisher: (公社)日本生化学会

  5. 東北メディカル・メガバンク計画における一般住民への遺伝情報回付

    大根田 絹子

    日本体質医学会雑誌　85　(3)　158-158　2023/08

    Publisher: 日本体質医学会

    ISSN： 1347-7137

  6. 関係学問の最前線(産業保健枠)職場における遺伝情報の取扱いと対応の実際～遺伝性腫瘍の仮想事例からの接近～【指定発言】前向きゲノムコホート参加者を対象とした遺伝性乳がん卵巣がんの遺伝情報回付

    大根田 絹子

    産業保健法学会誌　2　(1)　121-125　2023/06

    Publisher: (一社)日本産業保健法学会

    ISSN： 2758-2566

    eISSN： 2758-2574

  7. ゲノムコホート研究参加者5万人を対象としたBRCA1/2遺伝情報の回付と医療への連携

    濱中 洋平, 大根田 絹子, 川目 裕, 布施 昇男, 長神 風二, 鈴木 洋一, 山口 由美, 多田 寛, 原田 成美, 宮下 穣, 江幡 明子, 佐藤 未来, 柳垣 美歌, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集　31回　89-89　2023/06

    Publisher: (一社)日本乳癌学会

  8. 東北メディカル・メガバンク計画におけるバイオバンク事業について

    大根田絹子, 大根田絹子

    日本医療検査科学会春季セミナープログラム・抄録集　37th　2023

  9. Returning individual genomic results to prospective cohort study participants with hereditary breast and/or ovarian cancer syndrome

    大根田絹子

    産業保健法学会誌(Web)　2　(1)　2023

    ISSN： 2758-2574

  10. 東北メディカル・メガバンク計画バイオバンクのリソースを利用した論文と分譲実績の分析に基づいた利活用の傾向

    松原博子, 山口由美, 舘野穣, 信國宇洋, 大根田絹子

    日本遺伝子診療学会大会プログラム・抄録集　30th　2023

  11. バイオバンク・ネットワーク~ブース出展におけるバイオバンク利活用促進について

    長神風二, 井上真季子, 笠原直子, 永家聖, 信國宇洋, 大根田絹子, 荻島創一

    日本遺伝子診療学会大会プログラム・抄録集　30th　2023

  12. Identification and analysis of a distal Gata2 enhancer that is required for increasing Gata2 gene expression during mast cell and basophil maturation

    大森慎也, 鈴木未来子, 高井淳, 森口尚, 森哲哉, 大根田絹子

    日本分子生物学会年会プログラム・要旨集(Web)　46th　2023

  13. 【診療における薬理遺伝学検査の社会実装に向けて】一般住民を対象としたゲノムコホート研究参加者への薬理遺伝学検査の情報回付

    大根田 絹子

    医学のあゆみ　283　(7)　712-717　2022/11

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  14. マスト細胞における転写因子GATA2の高度転写活性化機序の解析

    大森 慎也, 高井 淳, 森口 尚, 森 哲哉, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　95回　1P-248　2022/11

    Publisher: (公社)日本生化学会

  15. 本邦における鉄代謝異常に伴う貧血に関する包括的疫学研究

    藤原亨, 大根田絹子, 佐々木克幸, 青木裕一, 工藤久智, 勝岡史城, 熊田和貴, 萩島創一, 山本雅之, 張替秀郎, 張替秀郎

    日本鉄バイオサイエンス学会学術集会プログラム・抄録集　46th　2022

  16. ゲノムコホート研究におけるBRCA1/2病的バリアント保持者への遺伝情報回付:遺伝情報回付による心理的・社会的影響の解析

    大根田絹子, 濱中洋平, 濱中洋平, 川目裕, 川目裕, 鈴木洋一, 鈴木洋一, 長神風二, 長神風二, 布施昇男, 布施昇男, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　67th (CD-ROM)　2022

  17. Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants

    徳永英樹, 安田純, 島田宗昭, 濱中洋平, 重田昌吾, 布施昇男, 勝岡史城, 荻島創一, 荻島創一, 山口由美, 寳澤篤, 川目裕, 大根田絹子, 青木洋子, 山本雅之, 八重樫伸生

    日本癌学会学術総会抄録集(Web)　81st　2022

  18. ゲノムコホート調査参加者に対する個人へのファーマコゲノミクス情報回付に関するパイロット研究

    大根田 絹子

    日本臨床薬理学会学術総会抄録集　42回　2-4　2021/12

    Publisher: (一社)日本臨床薬理学会

    eISSN： 2436-5580

  19. ゲノムコホート研究参加者へのBRCA1/2遺伝情報回付の取り組み

    大根田絹子, 濱中洋平, 濱中洋平, 川目裕, 川目裕, 鈴木洋一, 鈴木洋一, 長神風二, 布施昇男, 布施昇男, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　66th (CD-ROM)　2021

  20. マスト細胞遺伝子発現制御におけるGATA1/GATA2とPU.1の相互作用の解析

    大森 慎也, 大根田 絹子

    アレルギーの臨床　40　(12)　1024-1029　2020/11

    Publisher: (株)北隆館

    ISSN： 0285-6379

  21. 転写因子GATA2とPU.1による高親和性IgE受容体の発現と転写制御

    大森 慎也, 大根田 絹子

    生化学　92　(4)　587-590　2020/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  22. ゲノムコホート調査におけるゲノム薬理学(PGx)遺伝情報返却(回付)のパイロット研究

    濱中 洋平, 大根田 絹子, 布施 昇男, 川目 裕, 長神 風二, 平塚 真弘, 宇留野 晃, 櫻井 美佳, 平良 摩紀子, 鈴木 吉也, 鈴木 洋一, 山本 雅之

    日本遺伝カウンセリング学会誌　41　(2)　122-122　2020/06

    Publisher: (一社)日本遺伝カウンセリング学会

    ISSN： 1347-9628

  23. 東北メディカル・メガバンク計画における遺伝情報返却の課題

    濱中洋平, 濱中洋平, 大根田絹子, 布施昇男, 川目裕, 川目裕, 長神風二, 鈴木吉也, 鈴木洋一, 鈴木洋一, 佐藤政文, 平塚真弘, 櫻井美佳, 宇留野晃, 山口由美, 平良摩紀子, 山本雅之, 濱中洋平, 濱中洋平

    日本人類遺伝学会大会プログラム・抄録集　65th (CD-ROM)　2020

  24. ゲノムコホート調査参加者に対するゲノム薬理学(PGx)遺伝情報の返却(回付)-PGxの知識・理解に関する調査票解析

    大根田絹子, 布施昇男, 川目裕, 川目裕, 長神風二, 鈴木吉也, 鈴木洋一, 鈴木洋一, 佐藤政文, 櫻井美佳, 宇留野晃, 濱中洋平, 平良摩紀子, 平塚真弘, 山本雅之, 山本雅之

    日本人類遺伝学会大会プログラム・抄録集　65th (CD-ROM)　2020

  25. GATA2とPU.1は、異なる働きにより高親和性IgE受容体サブユニットFcεRIβ遺伝子の発現を制御する

    大森 慎也, 関田 将孝, 佐藤 太一, 石嶋 康史, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　92回　[1P-228]　2019/09

    Publisher: (公社)日本生化学会

  26. 骨髄由来マスト細胞においてGATA2はCebpa遺伝子座のK27me3化の維持に関与する

    大森 慎也, 養田 真理, 大杉 真甲, 大根田 絹子

    日本生化学会大会プログラム・講演要旨集　91回　[2P-227]　2018/09

    Publisher: (公社)日本生化学会

  27. BMMCsにおいてCebpaはGATA因子とPU.1の相互作用によって制御される

    大森 慎也, 島 武志, 養田 真理, 石嶋 康史, 大根田 絹子

    生命科学系学会合同年次大会　2017年度　[1P-0739]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  28. CRISPR/Cas9法によるGata2-136K領域を欠失した3T3-L1細胞の作製とその解析

    石嶋 康史, 大井田 晃莉, 大森 慎也, 大根田 絹子

    生命科学系学会合同年次大会　2017年度　[1P-0748]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  29. GATA2 is critical tor the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

    大森 慎也, 大根田 絹子

    臨床免疫・アレルギー科 = Clinical immunology & allergology　64　(4)　352-359　2015/10

    Publisher: 科学評論社

    ISSN： 1881-1930

  30. GATA2がCebpaの転写を抑制することが骨髄マスト細胞の分化形質維持に必要である

    大森慎也, 登丸菜月, 石嶋康史, 森口尚, 山本雅之, 大根田絹子

    日本分子生物学会年会プログラム・要旨集(Web)　37th　3P-0588 (WEB ONLY)　2014

  31. BACトランスジェニックマウスを用いた血球分化マスター転写因子GATA1の遺伝子発現制御機構の解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    生化学　85　(8)　720-720　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  32. GATA1は骨髄マスト細胞(BMMCs)の増殖と生存に必要である.

    植栗 幸洋, 大森 慎也, 石嶋 康史, 平林 優奈, 森口 尚, フィリップセン・シャック, 山本 雅之, 大根田 絹子

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0545　2010/12

    Publisher: (公社)日本生化学会

  33. Gata1遺伝子発現制御機構のBACトランスジェニックマウスを用いた解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0548　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  34. Gata1 deficiency in adult erythropoiesis

    大森 慎也, 大根田 絹子

    血液・腫瘍科　57　(6)　658-663　2008/12

    Publisher: 科学評論社

    ISSN： 0915-8529

  35. BACトランスジェニックマウスを用いたGata1遺伝子発現制御機構の解析

    高井 淳, 森口 尚, 鈴木 美来子, 大根田 絹子, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　2T3-11　2008/11

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  36. Gata1遺伝子発現制御領域の血球分化段階特異的な機能的貢献

    森口尚, 鈴木未来子, 高井淳, 大根田絹子, 山本雅之

    生化学　2008

    ISSN： 0037-1017

  37. G1HE-core contributes to the stage-specific expression of the Gata1 gene during erythroid development

    Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　180-180　2007/03

    DOI： 10.1016/j.bcmd.2006.10.135 　

    ISSN： 1079-9796

  38. Dynamic regulation of gata factor levels is more important than their identity

    Ferreira Rita, Wai Albert, Shimizu Ritsuko, Gillemans Nynke, Rottier Robbert, von Lindern Marieke, Ohneda Kinuko, Grosveld Frank, Yamamoto Masayuki, Philipsen Sjaak

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　171-172　2007/03

    DOI： 10.1016/j.bcmd.2006.10.117 　

    ISSN： 1079-9796

  39. モデル生物が切り開く造血発生研究の新展開 (発生システムのダイナミクス) -- (組織・器官形成)

    大根田 絹子, 山本 雅之

    蛋白質核酸酵素　50　(6)　633-637,495　2005/05

    Publisher: 共立出版

    ISSN： 0039-9450

  40. Self-association of GATA-1 is required for erythropoiesis in vivo.

    R Shimizu, K Ohneda, K Nishikawa, CD Trainor, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　34　(2)　122-122　2005/03

    ISSN： 1079-9796

  41. GATA1 function, a paradigm for transcription factors in hematopoiesis. International-journal Peer-reviewed

    Rita Ferreira, Kinuko Ohneda, Masayuki Yamamoto, Sjaak Philipsen

    Molecular and cellular biology　25　(4)　1215-27　2005/02

    DOI： 10.1128/MCB.25.4.1215-1227.2005 　

    ISSN： 0270-7306

  42. A minigene containing four discrete cis elements recapitulates GATA-1 gene expression in vivo.

    K Ohneda, R Shimizu, S Takahashi, JD Enge, M Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　31　(1)　157-157　2003/07

    ISSN： 1079-9796

  43. mafAノックアートマウスの解析

    ZHANG C, 森口尚, 梶原美和子, 大石久史, 浜田理人, 森戸直記, 大根田絹子, DOUGLAS ENGEL J, 山本雅之

    日本分子生物学会年会プログラム・講演要旨集　26th　2003

  44. Chronic overexpression of IGF-I and inhibition of spontaneous and irradiation-induced apoptosis in the mouse jejunum

    HR Wilkins, K Ohneda, KL Williams, CR Fuller, AJ D'Ercole, PK Lund

    GASTROENTEROLOGY　122　(4)　A371-A371　2002/04

    ISSN： 0016-5085

  45. Regulation of insulin gene transcription

    OHNEDA K.

    Sem Cell Dev Biol　11　227-233　2000

  46. Increased expression of nucleoside diphosphate kinases/nm23 in human diploid fibroblasts transformed by SV40 large T antigen or 60Co irradiation

    Kinuko Ohneda, Mitsugu Fukuda, Nobuko Shimada, Naoshi Ishikawa, Tateo Ichou, Kazuhiko Kaji, Takayoshi Toyota, Narimichi Kimura

    FEBS Letters　348　(3)　273-277　1994/07/18

    DOI： 10.1016/0014-5793(94)00623-7 　

    ISSN： 0014-5793

Show all ︎Show first 5

Research Projects 13

  1. IL-3誘発性の好塩基球前駆細胞増殖における転写因子GATA2の分子機能解明

    大根田 絹子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2024/04/01 - 2027/03/31

  2. Analysis of the molecular basis of Gata2 gene activation in mast cells

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2021/04/01 - 2024/03/31

  3. Analysis of the molecular basis of mast cell-specific gene transcription by Gata1/Gata2 and PU.1.

    Ohneda Kinuko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    2018/04/01 - 2021/03/31

    More details Close

    GATA1/GATA2 and PU.1 are known to function antagonistically during hematopoietic development. However, these factors are co-expressed in mast cells, and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FcεRI). The present study investigated the roles of GATA2 and PU.1 on Ms4a2 gene transcription. Gene ablation experiments revealed that GATA2 and PU.1 almost equally contributed to the Ms4a2 gene expression. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4 kb region downstream of the Ms4a2 gene, whereas the proximal -0.06 kb region was exclusively bound by GATA2. Furthermore, we showed that the ablation of the +10.4 kb region by genome editing abolished the Ms4a2 gene expression. Collectively, these results suggest that PU.1 plays central roles in the formation of active chromatin structure, whereas GATA2 directly activates the Ms4a2 promoter.

  4. Transcriptional regulation of mouse tryptase genes by GATA1 and GATA2 in mast cells.

    Kinuko Ohneda

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Takasaki University of Health and Welfare

    2015/04/01 - 2018/03/31

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    Mouse mast cell tryptase genes (Tpsg1, Tpsb2 and Tpsab1) are located at chromosome 17A3.3. In this study, we examined molecular basis of mast cell tryptase gene regulation by GATA1 and GATA2. Quantitative RT-PCR analysis showed that tryptase gene mRNA levels were significantly reduced by the loss of GATA factors in bone marrow mast cells (BMMCs). ChIP assays revealed that the GATA factors bind to the regions located at 72.8 and 84.3 kb upstream of Tpsb2 gene (referred to as region A and region B) in BMMCs. Deletion of region A using the CRISPR/Cas9 system resulted in a significant reduction of the Tpsb2 and Tpsg1 mRNA levels in MEDMC-BRC6 mast cells. Furthermore, CTCF and the cohesin subunit Rad21 binding to the regions between regions A and B was significantly reduced by the loss of GATA1 in BMMCs. Collectively, these results suggest that GATA factors play important roles for organizing active chromatin architecture at mouse tryptase genomic locus in mast cells.

  5. 骨髄球系細胞の系列転換における「遷移細胞」の解析

    大根田 絹子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 高崎健康福祉大学

    2013/04/01 - 2015/03/31

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    研究代表者らは、以前、マウス骨髄マスト細胞は、GATA2欠失によりマスト細胞の分化形質を失い未分化な形態を示すことを見いだした。このGATA2欠失細胞は、正常な血球分化の過程にはみられない不安定な「遷移状態」にあると考えられた。本研究は、この細胞を解析し、骨髄球系細胞の細胞系列転換機構を明らかにすることを目的として行った。研究結果の概要は、以下のとおりである。 GATA2欠失細胞は、マスト細胞にはほとんど発現していないC/EBPαを高発現しており、培養条件によってマクロファージや好中球様の細胞に系列転換した。一方、好塩基球や好酸球には分化しなかったが、一部の好塩基球特異的な遺伝子群の発現が増加していた。野生型BMMCにC/EBPαを過剰発現させると、C/EBPα の発現量依存的にGATA2mRNAの発現量が低下し、GATA2欠失細胞の表現型が一部再現された。GATA2とC/EBPαを同時に欠失させると、マクロファージや好中球に発現する遺伝子の発現増加は見られなくなったが、マスト細胞特異的な遺伝子の発現低下は観察された。BMMCとは異なり、腹腔細胞由来の培養マスト細胞（PMC）では、GATA2を欠失させてもC/EBPαの増加は見られなかった。これらの結果から、BMMCにおいて、GATA2とC/EBPαはお互いの発現を抑制している可能性が示唆された。GATA2欠失BMMCが正常な好塩基球に系列転換できなかったことから、好塩基球への分化にはGATA2が必要であると考えられた。

  6. Roles of GATA transcription factors in the development and function of mast cells

    OHNEDA Kinuko, ISHIJIMA Yasushi, OHMORI Shinya

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Takasaki University of Health and Welfare

    2012/04/01 - 2015/03/31

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    The present study demonstrates that targeted deletion of Gata1 has a minimal effect on the number and distribution of peripheral tissue mast cells in adult mice. Bone marrow derived mast cells (BMMCs) prepared from Gata1-null mice differentiated normally without affecting their degranulation activity. Microarray analyses showed that GATA1 knockdown BMMCs have a small impact on the mast cell-specific gene expression in most cases. However, the expression levels of mast cell tryptases in the mouse chromosome 17A3.3 were uniformly reduced in the GATA1 knockdown cells. In contrast to the observations in the Gata1-null BMMCs, GATA2 deficiency in BMMCs resulted in a significant loss of the mast cell fraction and a reduced expression of several mast cell-specific genes. Collectively, GATA2 plays a more important role than GATA1 in the regulation of most mast cell-specific genes, while GATA1 might play specific roles in mast cell functions.

  7. 造血系転写因子によるマスト細胞分化決定機構の解明

    大根田 絹子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 高崎健康福祉大学

    2011/04/01 - 2013/03/31

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    本研究は、血球系転写因子によるマスト細胞の分化制御機構を解明することを目的としている。前年度は、条件付Gata1ノックアウトマウスを用いた解析により、GATA1は分化したマスト細胞の形質維持に必須ではないことを明らかにした。一方、マウス骨髄マスト細胞(BMMC)では細胞分化とともに GATA2の発現が増加することから、GATA1の機能欠失をGATA2が代償している可能性が考えられた。 今年度は、この可能性を検証するために更に解析を進めた。野生型BMMCを用いたChIP解析では、保存されたGATA配列を有するマスト細胞特異的な遺伝子のプロモーター領域に、GATA1とGATA2の両方が結合していた。また、siRNAでGATA2の発現を抑制すると、GATA2を正常に発現している細胞では見られなかった、GATA1欠失によるマスト細胞特異的な遺伝子発現の低下が観察された。さらに、GATA2のDNA結合ドメインを誘導的に欠失するマウスからBMMCを作成し、GATA2の機能欠失解析を行ったところ、BMMCは、GATA2の機能欠失によりマスト細胞のマーカーであるc-KitとFceRIaの発現を消失し、未熟な骨髄球系細胞に特徴的なGr1やMac1を発現する細胞へと系列転換した。細胞の形態も明らかに変化し、マスト細胞に特徴的な顆粒が失われていた。GATA2機能欠失BMMCでは、GATA1の発現増加はみられず、Scl、 PU.1、 Runx1などの血球系転写因子の発現も変化しなかったが、野生型BMMCには発現していないC/EBPalphaの発現が著しく増加していた。 これらの結果から、GATA2は、GATA1と協調してマスト細胞特異的な遺伝子の発現を制御するのみならず、C/EBPalphaの発現を抑制することにより他の骨髄球系細胞への分化を抑制してマスト細胞の形質を維持していると考えられた。

  8. Roles of Gata1 in mature mast cells

    OHNEDA Kinuko, ISHIJIMA Yasushi, OHMORI Shinya

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Takasaki University of Health and Welfare

    2009 - 2011

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    The aim of this study is to clarify the roles of GATA1 in mature mast cells. We show that GATA1 and GATA2 are involved in mast cell degranulation through the control of phospholipase C-γ1(PLC-γ1) expression. Knockdown of GATA1 and/or GATA2 by specific siRNA significantly reduced antigen-induced degranulation and Ca^<2+> mobilization in the rat basophilic leukemia cell line RBL-2H3.RT-PCR analyses showed that PLC-γ1 expression was significantly decreased by this GATA factor repression. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that GATA factors directly activate PLC-γ1 gene transcription through a conserved GATA-binding motif that resides in the 5'-upstream sequence. Furthermore, we show that GATA2, but not GATA1 plays a major role in regulating PLC-γ1 expression in mast cells derived from mouse bone marrow.

  9. Roles of transcription factors for carcinogenesis and carcinogenesisdefense

    MASAYUKI Yamamoto, RITSUKO Shimizu, KINUKO Ohneda

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    2005 - 2009

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    In this study, we investigated roles transcription factors play on carcinogenesis and carcinogenesis defense in vivo, focusing on the Nrf2 and GATA transcription factors. We have found that co-operative function of Nrf2 and Keap1, which mediates cellular stress response, is important for the cancer carcinogenesis defense so that the failure in Nrf2-Keap1 system leads to the onset of cancer and poor prognosis. We have further found that deregulated function of GATA factors, which act as key molecules in hematopoietic homeostasis, causes leukemogenesis.

  10. Analysis of gata1 deficiency in postnatal erythropoiesis

    OHNEDA Kinuko, ISHIJIMA Yasushi, OHMORI Shinya

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Takasaki University of Health and Welfare

    2007 - 2008

  11. Regulation of Gata1 gene expression levels during erythroid cell development

    KINUKO Ohneda

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    2005 - 2006

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    Transcription factor GATA-1 is the master regulator of erythroid cell differentiation. Expression level of the Gata1 gene changes dynamically during erythroid differentiation, and this change is essential for the proper erythropoiesis. To investigate the molecular mechanism how Gata1 gene expression changes during the erythroid lineage development, we established a novel reporter transgenic mouse system utilizing bacterial artificial chromosome containing the Gata1 gene (Gata1-BAC). In the Gata1-BAC transgenic mice, reporter gene expression faithfully recapitulates temporal and spatial expression of the Gata1 gene in a copy number-dependent but integration position-independent manner. Since the core region (235 bp) of Gata1 gene hematopoietic enhancer (G1HE), which localizes at 3.9-kbp upstream of erythroid specific IE first exon, is highly conserved between human and mouse and appeared to be important in our plasmid transgenic mouse experiments, we analyzed reporter transgenic mouse lines harboring the G1HE-Core-deficient BAC reporter transgene. Results demonstrated that G1HE-Core is essential for up-regulation of the Gata1 gene throughout the erythroid differentiation. Especially, in the absence of G1HE-Core, the expression of Gata1 is abrogated in early erythroid progenitor (EEP) stage, which corresponds to BFU-E, and in erythroblasts. On the contrary, there remains G1HE-Core-independent expression of the Gata1 gene in late erythroid progenitor (LEP) stage, which contains to CFU-E and proerythroblasts. Mutational analyses further revealed that the conserved GATA-box in G1HE-Core is essential for this enhancer activity. Thus, analyses with the Gata1-BAC reporter transgenic mouse lines demonstrate for the first time that G1HE-Core directs the stage-specific expression of the Gata1 gene in vivo.

  12. Transcription factor regulation of malignant cell transformation and its repression

    YAMAMOTO Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: University of Tsukuba

    2003 - 2004

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    In this study we have studied transcription factor regulation of malignant cell transformation and its repression exploiting hematopoietic transcription factors and leukemia as a model system. GATA-1 is essential for the development of erythroid and megakaryocytic lineages and mutations leading to the production of N-terminus truncated form GATA-1 are frequently found in the Down syndrome-related acute megakaryoblastic leukemia (AMKL-DS) patients. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder that resembles myelodysplastic syndrome characterized by the accumulation of progenitors. We have demonstrated that GATA-1.05/X mice suffer from two distinct types of acute leukemias. Since GATA-1 is an X chromosomal gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the latter hematopoietic progenitors, low-level GATA-1 expression is sufficient to support survival, but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia cases have not been observed in GATA-1-null/X mutant mice and since transgenic expression of wild-type GATA-1 rescue GATA-1.05/X mice from the leukemia, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. In addition, wild-type GATA-1 promoted AMKL-DS leukemic cells to mature erythroid cells, but truncated form GATA-1 could not, suggesting that defect of GATA-1 is one of the leukemogenic factors.

  13. 転座関連遺伝子及び転写因子による細胞分化とがん化の分子機構

    瀬戸 加大, 森下 和広, 山本 雅之, 大根田 絹子, 鈴木 律朗

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 愛知県がんセンター(研究所)

    2000 - 2004

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    瀬戸は、粘膜関連リンパ組織(MALT)リンパ腫に特異的に認められる染色体転座、t(11,18)(q21,q21)に関与する遺伝子API2-MALT1について、造血器細胞における機能の解析をするために細胞株や骨髄幹細胞にAPI2-MALT1遺伝子を導入した。Hela細胞株や増殖因子依存性の細胞株ではUV刺激、抗がん剤などによるアポトーシスを抑制する能力があることが明らかとなった。また、API2-MALT1と相互作用する蛋白としてTRAF2、smac、HtrA2などアポトーシスを制御する蛋白を明らかにした。また、悪性リンパ腫のゲノム異常をアレイCGHで検索したところ、病型特異的なゲノム異常が存在することが明らかとなった。 森下は、Evi1転座関連遺伝子の機能を明らかにするためにEvi1遺伝子欠損マウスの造血発生異常を検討し、造血幹細胞の維持・増殖異常及び、血管発生異常を同定した。遺伝子発現解析にてGATA-2遺伝子の転写低下、プロモーター解析によりEvi1はGATA-2の直接の転写調節に係わることがわかった。Evi1は白血病細胞内にてGATA-2転写を亢進させ、白血病幹細胞の増殖維持に関係していることが示唆され白血病発症機構の一端を解明した。t(1,3)転座関連遺伝子としてEVI1遺伝子ファミリーであるMEL1遺伝子を単離し、機能解析によりEVI1と同様の転写因子機能を持っていることがわかり白血病発症機構も類似することが示唆された。

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